Metabolic reprogramming and metabolic rewiring have been used to describe the metabolic alterations in cancer cells where bioenergetics, anabolic biosynthesis and appropriate redox status are coordinated to promote cell proliferation and tumor growth. We believe that metabolic reprogramming represents software changes in cancer cells and describes metabolic alterations normally induced by growth factors in proliferative cells that are hijacked by oncogenic signals, whereas metabolic rewiring represents hardware changes in cancer cells and describes metabolic alterations that are newly forged due to neo-function of distinct oncogenic mutants, but not found in normal cells. Although increasing evidence emerges and suggests that different human cancers may share common metabolic properties, such as the Warburg effect, it is not clear whether distinct oncogene mutations, including oncogenes as well as tumor suppressor genes (TSGs), in different cancer types may require different metabolic properties for tumor development, and thus specifically rewire and reprogram cancer cell metabolism. We approached to this question by identifying unique metabolic vulnerability required by oncogenic BRAF V600E mutant in human melanoma cells, which are not required by other oncogenes such as NRas Q61R/K. We found that HMG-CoA lyase (HMGCL), a key enzyme in ketogenesis producing ketone bodies, is a synthetic lethal partner of BRAF V600E. HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukaemia cells in tissue samples from patients. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, HMGCL controls the intracellular levels of its product, acetoacetate, to promote activation of MEK-ERK signaling, where acetoacetate specifically enhances binding of BRAF V600E but not BRAF wild type to MEK. We also found that BRAF V600E may phosphorylate and activate a transcription factor Oct-1 to upregulate HMGCL in a MEK1-ERK independent manner. Moreover, a high-fat diet resulted in increased serum levels of acetoacetate but selectively promoted tumor formation of BRAF V600E-expressing melanoma cells in mice. Thus, we hypothesize that oncogenic BRAF V600E rewires metabolic and cell signaling networks and signals through Oct-1 to promote the HMGCL-acetoacetate axis that selectively enhances BRAF V600E-dependent tumor development. Three Specific Aims: (1) To determine whether a ketogenic diet (high-fat and low carbohydrate) would worsen the disease burden in diverse BRAF V600E-positive mouse models with melanoma or hairy cell leukemia; (2) To validate the HMGCL-acetoacetate axis as an alternative therapeutic target in treatment of BRAF V600E-positive human malignancies; (3) To elucidate the molecular mechanisms by which acetoacetate specifically promotes BRAF V600E-MEK1 binding, and active forms of BRAF including V600E mutant activate Oct-1.